Process for production of 1-[2-(benzimidazol-2-yl- thio)ethy]piperazine or salts thereof

ABSTRACT

This invention relates to a method for producing 1-[2-(benzimidazol-2-ylthio)ethyl]piperadine (5) or its salt by the following reaction scheme:  
                 
This invention enables efficient production of 1-[2-(benzimidazol-2-ylthio) ethyl]piperadine or its salt which is an intermediate in the production of a cyclic diamine compound which is useful as a ACAT inhibitor.

TECHNICAL FIELD

This invention relates to a method for producing1-[2-(benzimidazol-2-ylthio)ethyl]piperadine or its salt, which is anintermediate in producing ACAT inhibitor.

BACKGROUND OF THE INVENTION

Acyl coenzyme A: cholesterol acyltransferase (ACAT) is an enzyme whichcatalyzes synthesis of cholesterol ester from cholesterol, and it playsan important role in the metabolism of the cholesterol and itsabsorption from the digestive tract.

Recent studies have revealed that elevation of blood cholesterol levelcan be effectively suppressed by inhibiting the activity of ACAT insmall intestine and liver, and quite a number of studies have beenconducted on ACAT inhibitor.

On the other hand, the present inventors focused the study on ACAT invascular wall, and studied on the selective inhibitors against this typeof ACAT. It was then found that azole compounds having a cyclic diaminestructure, and in particular, a cyclic diamine compound represented bythe following formula (7):

wherein Ar represents an optionally substituted aryl or heteroarylgroup, as well as its salt exhibit reduced side effects, high solubilityin water, and excellent oral absorption, and that such compound is welladapted for use as a therapeutic drug for hyperlipidemia andarteriosclerosis. As a result, the present inventors have filed a PCTapplication for an invention associated with azole compounds includingthe compound (7) (WO98/54153).

This patent application has demonstrated that the compound (7) can beproduced by the method as represented by the following reaction scheme.

In this method, the compound (7) is produced in the five steps asdescribed below by starting from 1-(2-hydroxyethyl) piperazine (6),namely,

-   -   by protecting amino group of the 1-(2-hydroxyethyl)        piperazine (6) with tert-butoxycarbonyl (Boc) group to produce        1-(tert-butoxycarbonyl)-4-(2-hydroxyethyl) piperazine (1a) (Step        a); converting hydroxyl group of this compound (1a) to        methanesulfonyloxy group to produce compound (2a) (Step b);        reacting this compound (2a) with 2-mercaptobenzimidazole (3) in        the presence of a base to produce        1-[2-(benzimidazol-2-ylthio)ethyl]-4-(tert-butoxycarbonyl)        piperazine (4a) (Step c); removing the Boc group for        deprotection by using trifluoroacetic acid to produce        1-[2-(benzimidazol-2-ylthio)ethyl]piperadine.3 trifluoroacetic        acid (5a) (Step d); and reacting the compound (5a) with a bromo        derivative (8) to thereby produce the compound (7) or its salt        (Step e).

This production method, however, suffered from the problems including(i) di-tert-butyl dicarbonate, which is the expensive reagent used inthe amino group protection; (ii) difficulty in Step a of purifying thetarget compound (1a) by distillation, which is the convenientpurification method; (iii) difficulty of producing the compound (1a) inhighly anhydrous condition as required by the following Step b becauseof the difficulty in the purification by distillation; (iv) poorstability of the mesyl derivative (2a) which is used as the startingmaterial in Step c, and difficulty in reproducing the yield of the smallscale synthesis in the large scale synthesis; and (v) insufficient yieldin the deprotection reaction of Step d.

SUMMARY OF THE INVENTION

The present invention relates to provide an idustrially advantageousmethod for producing 1-[2-(benzimidazol-2-ylthio)ethyl]piperadine (5) orits salt which is an intermediate in producing the cyclic diaminecompound (7) or its salt.

In view of the situation as described above, the present inventors havemade an intensive study, and found that, as shown in the followingsynthesis scheme, if 1-[2-(benzimidazol-2-ylthio)ethyl]piperadine or itssalt (5) is produced by converting hydroxyl group of1-formyl-4-(2-hydroxyethyl) piperazine (1) to benzimidazol-2-ylthiogroup, and then deprotecting formyl group, yield as well as purity canbe improved by more convenient purification process compared to theprocess using Boc for the amino protective group. The present inventionis based on such a finding.

More specifically, the present invention provides a method for producing1-[2-(benzimidazol-2-ylthio)ethyl]piperadine represented by formula (5)or its salt comprising the steps of converting hydroxyl group in1-formyl-4-(2-hydroxyethyl)piperazine represented by formula (1) to aleaving group to produce a compound represented by formula (2), reactingthis compound with 2-mercaptobenzimidazole (3) in the presence of a baseto produce 1-[2-(benzimidazol-2-ylthio)ethyl]-4-formylpiperazinerepresented by formula (4), and detaching the formyl group to producethe 1-[2-(benzimidazol-2-ylthio)ethyl]piperadine represented by formula(5).

Use of the production method of the present invention will enableefficient production of the 1-[2-(benzimidazol-2-ylthio)ethyl]piperadineor its salt (5), and hence, the cyclic diamine compound (7) or its saltwhich is useful in medical applications is produced in a commerciallymore advantageous manner at a more stable yield compared to theconventional production method.

BEST EMBODIMENTS FOR CARRYING OUT THE INVENTION

The leaving group represented by “X” in the compound (2) of the presentinvention is a group like sulfonyloxy group or a halogen atom which isreadily replaceable, and examples include sulfonyloxy groups such asmethanesulfonyloxy, benzenesulfonyloxy, chloromethanesulfonyloxy,ethanesulfonyloxy, propanesulfonyloxy, and p-toluenesulfonyloxy, andhalogen atoms such as chlorine atom, bromine atom, and iodine atom.Among them, preferred is methanesulfonyloxy group.

The compound (5) of the present invention may form an acid additionsalt, and examples of such salt include inorganic acid salts such ashydrochloride, sulfate, nitrate, and phosphate, and organic acid saltssuch as methanesulfonate, maleate, fumarate, citrate, andtrifluoroacetate.

In addition, the compound (5) is not limited to the non-solvate type,and also included are a hydrate and a solvate having water, alcohol, orother solvent used in the production and purification added thereto.

[Step 1]

Exemplary processes which may be used in converting the hydroxyl groupof compound (1) to the leaving group include conversion of the hydroxylgroup to a sulfonyloxy group or a halogen atom.

Typically, conversion to a sulfonyloxy group may be accomplished byreacting the compound (1) with chloride or anhydride of sulfonic acid ina solvent at a temperature of 0° C. to room temperature in the presenceof a base.

Examples of the sulfonic acid in the sulfonic acid chloride or sulfonicacid anhydride include alkyl sulfonic acids such as methanesulfonic acidand ethanesulfonic acid and aryl sulfonic acids such as benzene sulfonicacid and p-toluenesulfonic acid.

Examples of the base used include triethylamine,N,N-diisopropylethylamine, pyridine, and 4-dimethyl aminopyridine, andexamples of the solvent used include chloroform, methylene chloride,acetonitrile, tetrahydrofuran, ethyl acetate, benzene, toluene, anddimethylformamide.

The conversion of the hydroxyl group to a halogen atom is preferablyaccomplished by using a chlorinating or brominating agent such asphosphorus oxychloride, phosphorus pentachloride, triphenylphosphinedichloride, triphenylphosphine dibromide, triphenylphosphite dichloride,triphenylphosphite dibromide, phosphorus tribromide, thionyl chloride,or triphenylphosphine and carbon tetrachloride; triphenylphosphine andcarbon tetrabromide; methanesulfonyl chloride and 4-dimethylaminopyridine; and the like in the absence of the solvent or in thesolvent such as dichloromethane, chloroform, dichloroethane, pyridine,or tetrahydrofuran at 0 to 120° C.

[Step 2]

The reaction between compound (2) and 2-mercaptobenzimidazole (3) may beaccomplished in a solvent and in the presence or absence of a base and acatalyst.

The solvent used is not particularly limited, and examples includedimethyl formamide, dimethyl sulfoxide, methylene chloride, chloroform,tetrahydrofuran, toluene, acetone, and acetonitrile, which may be usedalone or in combination of two or more.

Examples of the base used include inorganic bases, for example, alkalinemetal hydroxides such as sodium hydroxide and potassium hydroxide;alkaline metal carbonates such as sodium carbonate and potassiumcarbonate; alkaline metal hydrogencarbonates such as sodiumhydrogencarbonate and potassium hydrogencarbonate; as well as organicbases such as pyridine, triethylamine, N,N-diisopropylethylamine,N-methyl morpholine, and N,N-dimethylaniline.

Exemplary catalysts include crown ethers such as 18-crown-6 andquarternary ammonium salts such as tetrabutylammonium chloride,tetrabutylammonium bromide, tetrabutylammonium iodide,tetrabutylammonium hydrogensulfate, and benzyltrimethylammonium bromide.Among them, preferred is use of 18-crown-6.

The reaction is generally accomplished at 0 to 120° C., and preferablyat 20 to 100° C. for 1 to 12 hours, and preferably for 1 to 3 hours.

The target compound (4) exhibits good crystallization, and it can bereadily purified by crystallization. In addition, the target compound isobtainable by this reaction at a high yield and at a high purity in theindustrial scale production, since the reaction in the small scaleproduction is well reflected to such industrial scale production.

[Step 3]

The 1-[2-(benzimidazol-2-ylthio)ethyl]piperadine (compound (5)) or itssalt can be obtained by removing the formyl group of the thus obtainedcompound (4).

The removing of the formyl group may be accomplished by adding an acidto the compound (4) in a solvent, and allowing the reaction to proceedat 0° C. to 100° C. The solvent used may be an alcoholic solvent such asmethanol, ethanol, or isopropylalcohol, benzene, toluene, ethyl acetate,or the like, which may optionally contain water, and the acid used maybe hydrochloric acid, sulfuric acid, or the like.

The cyclic diamine compound (7) or its salt can be produced at a highefficiency by introducing a bromo derivative (8) to the amino group ofthe thus obtained compound (5) or its salt in the presence of a baseaccording to the method described in Patent Document 1.

The 1-formyl-4-(2-hydroxyethyl)piperazine (1), which is the startingmaterial of the present invention, can be produced by converting aminogroup of 1-(2-hydroxyethyl)piperazine (6) to formyl group by a knownmethod (Arzneim.Forsch 12,937-941(1962)) using methyl formate. Morespecifically, methyl formate may be added to the compound (6), and thereaction may be allowed to proceed at room temperature to refluxtemperature for 1 to 48 hours. Use of such reaction readily yields thecompound (1) at a high yield and at a high purity when it is purified bydistillation. In addition, use of methyl formate enjoys the merits oflow cost and considerable commercial availability.

Alternatively, compound (1) may be synthesized by such reaction as thereaction of 1-formylpiperazine with ethylene oxide, or the reaction of1-formylpiperazine with ethylene halohydrin or the ethylene halohydrinprotected by hydroxyl group in the presence of a base, or the like (Whenthe protected halohydrin is used, the reaction of the leaving group andthe removal of the protective group are simultaneously conducted)

EXAMPLES

The present invention is described in further detail by referring to thefollowing Examples.

Example 1 Production of1-[2-(benzimidazol-2-ylthio)ethyl]-4-formylpiperazine

1-formyl-4-(2-hydroxyethyl)piperazine was synthesized from1-(2-hydroxyethyl)piperazine by the method described in a document(Arzneim. Forsch 12, 937-941 (1962)). To a solution of1-formyl-4-(2-hydroxyethyl)piperazine (1.70 kg) in dimethyl formamide(DMF) (11 kg) were added triethylamine (1.52 kg) and 4-dimethylaminopyridine (0.13 kg), and while stirring this mixture in an ice bath,methanesulfonyl chloride (1.54 kg) was added dropwise to this mixtureover a period of 50 minutes, and the mixture was stirred in an ice bathfor 25 minutes. After the completion of the reaction, the insolublecontent was removed, and the residue was washed with DMF (1.6 kg×2). Thefiltrate and the washing solution were added to a mixed solution of DMF(1.63 kg), 2-mercaptobenzimidazole (1.61 kg), potassium carbonate (1.63kg), and 18-crown-6 (0.28 kg) at 80° C., and the mixture was stirred at80° C. for 1.5 hours. After adding water to the reaction solution, thesolution was concentrated under reduced pressure, and extracted withchloroform (13 kg×3). The organic layer was washed with saturatedaqueous sodium chloride, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The resulting crude product wascrystallized from methanol-diisopropyl ether to give 1.92 kg of1-[2-(benzimidazol-2-ylthio)ethyl]-4-formylpiperazine (yield 62%) as acolorless crystalline powder. Another 367 g of1-[(2-(benzimidazol-2-ylthio)ethyl]-4-formylpiperazine (yield 11.8%) wasobtained from the mother liquor of crystallization by repeating theprocedure. Total yield was 2.28 kg (yield 74%).

Melting point: 146-148° C. IR (KBr) cm⁻¹: 3440, 3049, 1619, 1441, 742.¹H-NMR (CDCl₃): 2.62 (4H, dt, J=10.5, 5.3 Hz), 2.91 (2H, t, J=6.1 Hz),3.37 (2H, t, J=6.1 Hz), 3.46 (2H, t, J=5.0 Hz), 3.65 (2H, t, J=5.0 Hz),7.18 (1H, dd, J=7.3, 3.0 Hz), 7.21 (1H, dd, J=7.3, 3.0 Hz), 7.41-7.58(2H, m), 8.06 (1H, s). MS (m/z): 290 (M⁺, 3.2), 140 (100). Elementaryanalysis: as C₁₄H₁₈N₄OS Calculated: C, 57.91; H, 6.25; N, 19.29; S,11.04. Found: C, 57.78; H, 6.30; N, 19.12; S, 11.15.

Example 2 Synthesis of 1-[2-(benzimidazol-2-ylthio)ethyl]piperadine.3hydrochloride

1-[2-(benzimidazol-2-ylthio)ethyl]-4-formylpiperazine (1.92 kg) wassuspended in methanol (4.5 kg), and 12N hydrochloric acid (2.9 kg) wasadded, and the mixture was stirred at 40° C. for 3 hours. To thereaction solution was added chloroform (17 kg), and the precipitatedcrystals were collected by filtration. The crystals were washed withchloroform to give 2.38 kg of1-[2-(benzimidazol-2-ylthio)ethyl]piperadine.3 hydrochloride (yield 97%)as colorless crystalline powder.

Melting point: 241-246° C. IR (KBr) cm⁻¹: 3374, 2938, 2647, 1630, 1522.¹H-NMR (DMSO-d₆): 3.37-3.50 (4H, m), 3.43-3.57 (4H, m), 3.54 (2H, t,J=7.0 Hz), 3.81 (2H, t, J=7.0 Hz), 7.31 (2H, dd, J=5.9, 3.3 Hz), 7.59(2H, dd, J=5.9, 3.3 Hz), 9.73 (2H, br s). MS (m/z): 262 (M⁺-3HCl, 3.1),140 (100). Elementary analysis: as C₁₃H₁₈N₄S.3HCl Calculated: C, 42.00;H, 5.69; N, 15.07. Found: C, 41.87; H, 5.62; N, 14.98.

Comparative Example 1 Production of1-tert-butoxycarbonyl-4-(2-hydroxyethyl)piperazine (1a)

The synthesis was conducted according to the method described in U.S.Pat. No. 4,247,549.

Comparative Example 2 Production of1-[2-(benzimidazol-2-ylthio)ethyl]-4-tert-butoxycarbonyl piperazine (4a)

Triethylamine (1.04 g, 10.3 mmol) and 4-dimethyl aminopyridine (104 mg,0.854 mmol) were added to a solution of1-tert-butoxycarbonyl-4-(2-hydroxyethyl)piperazine (2.00 g, 8.54 mmol)in tetrahydrofuran (THF) (30 mL) in an ice bath, and the solutes weredissolved by stirring. Methanesulfonyl chloride (1.37 g, 12.0 mmol) wasadded dropwise to the solution in the ice bath over a period of 5minutes with stirring, and the mixture was stirred for 1 hour in an icebath. After the completion of the reaction, the insoluble content wasremoved by filtration, and the thus removed insoluble content was washedwith THF (10 mL×2). The filtrate and the washing solution were combinedand concentrated under reduced pressure to such degree thatsubstantially no solvent was left. The concentrate was diluted with DMF(20 mL). To the solution was added 2-mercaptobenzimidazole (1.41 g, 9.39mmol), potassium carbonate (1.77 g, 12.8 mmol), and 18-crown-6 (226 mg,0.854 mmol), and the mixture was stirred at 80° C. for 3 hours. Thereaction solution was concentrated under reduced pressure, and theresulting concentrate was diluted and separated with ethyl acetate (10mL) and water (50 mL). The aqueous layer was further extracted withethyl acetate (10 mL×2), and the extract was combined with the organiclayer, washed with saturated aqueous sodium chloride, and dried overanhydrous sodium sulfate. It was then purified by silica gel columnchromatography (chloroform/methanol saturated with ammonia=40/1) to give1-[2-(benzimidazol-2-ylthio)ethyl]-4-tert-butoxycarbonyl piperazine 2.02g (64%) as colorless powdery crystals.

Melting point: 175-176° C. IR(KBr)cm⁻¹: 3433, 1695, 1619, 1591, 1517.¹H-NMR (CDCl₃): δ 1.49 (9H, s), 2.64 (4H, t, J=5.0 Hz), 2.96 (2H, t,J=5.4 Hz), 3.26 (2H, t, J=5.4 Hz), 3.61 (4H, t, J=5.0 Hz), 7.17-7.22(2H, m), 7.40-7.65 (2H, m). Elementary analysis: C₁₈H₂₆N₄O₂S Calculated:C, 59.64; H, 7.23; N, 15.46. Found: C, 59.63; H, 7.22; N, 15.30.

Comparative Example 3 Production of1-[2-(benzimidazol-2-ylthio)ethyl]piperadine.3 trifluoroacetate (5a)

1-[2-(benzimidazol-2-ylthio)ethyl]-4-tert-butoxycarbonyl piperazine(13.83 g, 38.15 mmol) was dissolved in trifluoroacetic acid (75 mL) inan ice bath, and the mixture was stirred at the same temperature for 30minutes, and after elevating the temperature to room temperature, themixture was stirred for another 40 minutes. The reaction solution wasconcentrated under reduced pressure, and the resulting crystals wererecrystallized from methanol-diethyether to give 15.24 g of1-[2-(benzimidazole-2-ylthio)ethyl]pyperadine.3 trifluoroacetate (66%)as pale yellow powdery crystals.

Melting point: 146-148° C. IR(KBr)cm⁻¹: 3572, 3512, 1675, 1619, 1536,1189, 1132. ¹H-NMR (DMSO-d₆): δ 3.05-3.11 (4H, m), 3.15 (2H, t, J=6.3Hz), 3.19-3.27 (4H, m), 3.55 (2H, t, J=6.3 Hz), 7.16-7.22 (2H, m),7.46-7.52 (2H, m), 8.75-9.10 (2H, m). Elementary analysis::C₁₉H₂₁F₉N₄O₆S Calculated: C, 37.75; H, 3.50; N, 9.27. Found: C, 37.56;H, 3.67; N, 9.20.

As demonstrated above, the production method of the present inventionusing the 1-formyl-4-(2-hydroxyethyl)piperazine could improve both theyield (steps 2 and 3) and the convenience of the purification (step 2)over the conventional production method using the1-(tert-butoxycarbonyl)-4-(2-hydroxyethyl)piperazine. In addition, incontrast to the conventional method wherein increase in the productionscale had been associated with the decrease in the yield (note that theyield of compound (4a) was 64% when 2 g of compound (1a) was used whilethe yield dropped to 26% when 50 g of compound (1a) was used), theproduction method of the present invention is free from such loss in theyield with the increase in the production scale, and similar yields areobtained in both the industrial scale production and the small scaleproduction.

1. A method for producing 1-[2-(benzimidazol-2-ylthio)ethyl]piperadinerepresented by the following formula (5):

or its salt, comprising the steps of: converting hydroxyl group in1-formyl-4-(2-hydroxyethyl) piperazine represented by the followingformula (1):

 to a leaving group to produce a compound represented by the followingformula (2):

 wherein X represents a leaving group; reacting this compound with2-mercaptobenzimidazole (3) to produce1-[2-(benzimidazol-2-ylthio)ethyl]-4-formylpiperazine represented by thefollowing formula (4):

 and removing the formyl group therefrom.
 2. The method according toclaim 1 wherein the 1-formyl-4-(2-hydroxyethyl) piperazine representedby the following formula (1):

is produced by converting amino group of 1-(2-hydroxyethyl) piperazinerepresented by the following formula (6)

to formyl group.